Celiac disease (CD) is a common, familial autoimmune, disease with significant morbidity if untreated. The prevalence of CD in the US is 1:250 and the ratio of symptomatic to asymptomatic cases is between 1:5 and 1:7. Before the advent of serological testing, it was considered a rare disease. Complications of CD include lymphoma, osteoporosis, anemia, and seizures. The only treatment is a gluten-free diet, which will improve symptoms, but recurrence of symptoms and complications may occur after minor dietary indiscretions. The objective of our previous grant was to localize non-HLA genes for CD. We created a resource of families, characterized CD cases at HLA, and found suggestive linkage evidence in several regions. In this proposal, we seek to further localize non-HLA gene(s) responsible for CD. To accomplish this goal, we will: 1) continue to collect families with multiple cases of CD and will include inbred CD Bedouin families with our Israeli collaborator; 2) perform a genome-wide search and linkage analysis in the Bedouin and US families; 3) follow-up genetic regions with evidence for linkage from the genome-wide analysis through a multi-stage approach of additional genotyping and more complex statistical analysis; and 4) refine localization in regions with significant evidence for linkage by a combination of transmission disequilibrium testing and recombinant mapping. The families we have continued to collect have enhanced our total resource. We now have one of the largest, most powerful family resources with which to localize genes for this complex disease. Identification of genes for CD will lead to a better understanding of the disease and its associated autoimmune diseases. Furthermore, more detailed knowledge about genes causing CD could lead to therapeutics to reduce the diet restrictions and morbidity of celiac disease.